ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3698C>T (p.Ala1233Val) (rs745700206)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214873 SCV000273647 uncertain significance Hereditary cancer-predisposing syndrome 2016-03-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000473952 SCV000549534 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-15 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 1233 of the BRCA2 protein (p.Ala1233Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs745700206, ExAC 0.01%). This variant has been observed in an individual affected with lung squamous cell carcinoma (PMID: 26689913), in individuals with pancreatic cancer (PMID: 28767289, 29309945) and in an individual with breast cancer in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 230195). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000486250 SCV000572073 uncertain significance not provided 2018-05-03 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.3698C>T at the cDNA level, p.Ala1233Val (A1233V) at the protein level, and results in the change of an Alanine to a Valine (GCT>GTT). Using alternate nomenclature, this variant would be defined as BRCA2 3926C>T. This variant has been reported in an individual with squamous cell carcinoma of the lung and an individual with pancreatic cancer (Lu 2015, Shindo 2017). BRCA2 Ala1233Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). BRCA2 Ala1233Val is located in the BRC2 domain and the RAD51 binding domain (Cole 2011, Roy 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA2 Ala1233Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000214873 SCV000688828 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-29 criteria provided, single submitter clinical testing

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